New basically substituted benzylbenzimidazoles



United States Patent Q P NEW BASICALLY SUBSTITUTED'BENZYL- BENZMDAZGLES Karl Hotfmann, Binningen, and Alfred Hunger, .lindrich Kebrle, and Alberto Rossi, Basel, Switzerland, assignors, to Ciba Pharmaceutical Products Inc, Surnmit, NJ.

No Drawing. Filed Nov. 4, 1959, Ser. No. 850,771 Claims priority, application Switzerland Aug. 30, 1957 9 Claims. (#Cl. 266-3692) This invention provides benzimidazoles of the formula R -N OoHz-Ri R1 -N 49H: (1H, 1!I(C2H5)2 v wherein R and R stand for a member selected from the group consisting of hydrogen, chlorine and the methyl group, and R for a member selected from the group consisting of lower alkoxy, lower alkylmercapto, lower alkyl and lower alkanoyl, said lower alkyl and alkoxy and alkyl mercapto groups being especially methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, methylmercapto, ethylmercapto, propylmercapto and butylmercapto, lower alkanoyl particularly 'acetyl and propionyl, and therapeutically useful acid addition salts thereof.

The new compounds possess good analgesic properties which are superior to those of known benzimidazoles such as described by Novelli, Chem. Abstracts, vol. 49, col. 1021 (1955). They are also blockers of spinal polysynaptic transmission. The new compounds are therefore useful as medicaments especially as analgetics.

The new benzimidazoles can be made by methods in themselves known, for instance by subjecting to ring closure an ortho-(R'NH)-aniline or an appropriate N-substituted derivative thereof, in which R represents the fl-diethylaminoethyl group or a residue convertible into such group, for example, the B-hydroxyethyl group.

The residue convertible into the fi-diethylaminoethyl' group is subsequently'so converted, in the case of the fl-hydroxyethyl group, for example, by chlorination and subsequent reaction with diethylaminer Thus, for example, ortho-(,B-diethylamino-ethylamino)-aniline may be subjected'directly or in stages to ring closure with a para-R -substituted phenylacetic acid or a reactive functional derivative thereof, especially an ester thereof with an alcohol capable of being split ofi easily, or an iminoether thereof.

. Depending on the procedure used the new compounds are obtained as the freebases or salts thereof. From the salts the free bases can be obtained by methods in themselves known. From the free bases salts can be 2,986,696 Patented Apr. 18, 1961 whichcontain the compound or a salt thereof in admixture with a pharmaceutical organic or inorganic, solid or liquid carrier suitable for enteral, parenteral or topical administration. For making the carriers there are used substances which do not react with the new compounds, for example, water, gelatine, lactose, starch, magnesium stearate, talc, vegetable oils, benzyl alcohols, gums, polyalkylene glycols, white petroleum jelly, cholesterol or other known carrier for medicaments. The pharmaceutical preparations may be, for example, in the form of tablets, dragees, salves, creams or in liquid form as solutions, suspensions orv emulsions. If desired they may be sterilized and/or may contain auxiliary substances, such as preserving, stabilizing, wetting or emulsifying agents, salts for regulating the osmotic pressure or buffers. They may also contain other therapeutically valuable substances.

This is a continuation-in-part application of our applications Serial No. 752,394, filed August 1, 1958; Serial No. 752,404, filed August 1, 1958; Serial No. 753,426, filed August 6, 1958; Serial No. 753,428, filed August 6, 1958; Serial No. 762,229, filed September 22, 1958; and Serial No. 763,436, filed September 26, 1958, all now abandoned.

The following examples illustrate the invention:

Example 1 To a solution of the imino ether hydrochloride of pmethylphenylacetic acid, obtained from 6.56 grams of p-methyl-benzyl cyanide, 2.9 cc. of absolute alcohol and 50 cc. of chloroform by the introduction of dry hydrochloric acid gas at -10 C. and allowing to stand at 25 C. for 16 hours, are added 10.5 grams of 2-(,B-diethylamino-ethylamino)-aniline and the whole is'stirred for 16 hours under reflux. The reaction mixture is evaporated under vacuum, the residue dissolved in aqueous hydrochloric acid, the acid solution, washed with ether, rendered alkaline with aqueous ammonia, then extracted with chloroform and the chloroform'extract, after washing with sodium carbonate solution and drying over magnesium sulfate, evaporated. The residue is distilled at l90200 C. under 0.2 mm. pressure. From the resulting l (B diethylamino ethyl) 2 (p methyl benzyl)- benzimidazole, an aqueous solution of its hydrochloride can be obtained by dissolving in the; calculated quantity of hydrochloric acid.

- ethyl phenyl acetic acid obtained from 7.25 grams of made by reaction with acids suitable for making therapeutically useful salts for example, hydrohalic acids, sulfp-ethyl-benzyl cyanide, 2.9 cc. of absolute alcohol and 50 cc. of chloroform by, the introduction of dry hydrochloric acid gas at '10 C. and allowing to stand at 25 C. for 16 hours, are added 10.35 grams of 2-(flfdiethylamino-ethylamino)-aniline and the whole is stirred for lo hoursunder reflux. The reaction mixture is evaporated under vacuum, the residue dissolved in aqueous hydrochloric acid, the acid solution, washed Withcther,

rendered alkaline with aqueous ammonia, then extracted vwith chloroform and the chloroform extract, after washing with sodiumv carbonate solution and drying over I magnesium sulphate, evaporated. The residue is distilled furic acid, nitric acid, phosphoric acid, thiocyanic acid, I

acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, malic acid, methane sulfonic acid, ethane The starting materials areknown or can be made by methods in themselves known.

The new (:ompoundshreuseful as medicaments, for

sulting at ZOO-210 C. under 0.1 mm. pressure. From therel-( ,B-diethylamino-ethyl) -2- p-ethyl-benzyl) -b enzimidazole, an aqueous solution ofits hydrochloride can :sulfonic acid, hydroxyethane sulfonic' acid-benzene or toluene sulfonic acid or a therapeutically. active acid.

hydrochloric acid.

bejobtained by dissolving in the calculated. quantityof p Example v I I To {Solution of the imino ether hydrochloride of ppropylpheny-l acetic acid, obtained; from 8.0; grams of 205215 C. under 0.2 mm. pressure.

p-propyl-benzyl cyanide, 2.9 cc. of absolute alcohol and 50cc. of chloroform by the introduction of dry hydrochloric acid gas at 10 C. and allowing to stand at 25 C. for 16 hours, are added 10.35 grams of 2-(fl-diethylan-iino-ethylamino)-aniline and the whole is stirred for 16 hours under reflux. The reaction mixture is evaporated under vacuum, the residue dissolved inaqueous hydrochloric acid, the acid solution, washed with ether, rendered alkaline with aqueous ammonia, then extracted with chloroform and the chloroform extract, after washing with sodium carbonate solution and drying over magnesium sulfate, evaporated. The residue is distilled at From the resulting l-(fi-diethylamino-ethyl) 2-(p-propyl-benzyl)-benzimidazole, an aqueous solution of its hydrochloride can be obtained by dissolving in the calculated quantity of hydrochloric acid.

The p-propyl-benzyl cyanide required as starting material is prepared in a manner analogous to that of G. S. Skinner et al., I. Am. Chem. Soc. 73, 2230 (1951), from propyl-benzene by way of p-propyl-benzyl chloride (3.1. 112 C. under 15 mm.) and hasthe boiling point 142 C. under 13 mm. pressure.

Example 4 1 (B diethylamino ethyl) 2 (p-acetyl-benzyl)- benzimidazle.To a solution of the imino ether hydrochloride of p-acetylphenyl acetic acid, obtained from 15.9 grams of p-acetyl-benzyl cyanide, 5.8 ml. of alcohol and 100 ml. of chloroform by the introduction of dry hydrochloric acid gas at 10 C. and allowing to stand at 25 Example 5 20.7 grams of 2-(fi-dicthylamino-ethylamino)aniline are added dropwise to a solution in chloroform of the iminoether hydrochloride of para-ethoxy-phenylacetic acid, obtained from 16.1 grams of para-ethoxy-benzyl cyanide and 5.8 ml. of absolute alcoholin 100 ml. of chloroform by introducing dry hydrogen chloride gas at C. and allowing the whole to stand at 25 C. for 16 hours. The whole is then boiled under reflux for 16 hours. The reaction mixture is extracted with aqueous hydrochloric acid, the acid solution is rendered alkaline with ammonia solution, then extracted with chloroform, and the extract is evaporated, after being washed with sodium carbonate solution and dried with magnesium sulfate. The 1 (fl diethylaminoethyl)-2- (para-ethoxybenzyl) benzimidazole so obtained melts at 65-66" C. after recrystallization from ether..

The hydrochloride, obtained by dissolving the base in alcohol, adding two equivalents of alcoholic hydrochloric acid and concentrating the mixture, melts at 118-120 Example 6 p 20.7 grams of 2-(fi-diethylamino-ethylamino)-aniliue of 'para-methoxy-phenylacetic acid, obtained from 14.7 grams of para-methoxy-benzyl cyanide, 5.8 cc. of absolute alcoholin 100 cc. of chloroform by the introduction of dry hydrogen chloride gas at 10 C. and allowing the whole to stand at 25 C. for 16 hours. The whole.

'is then boiled under reflux'for' 16 hours. The reaction mixture is evaporated in vacuo, the residue is dissolved in aqueous hydrochloric acid, the acid solution is washed with ether, rendered alkaline with aqueous ammonia solution, extracted with chloroform, and the extract solution is evaporated after being washed with sodium carbonate solution and dried with magnesium sulfate. The crude l-(fi-dicthylaminoethyl)-2(pararncthoxybenzyl) benzimidazole so obtained is converted into its hydrochloride, melting at 150l5 1 C. by dissolving the crude base in alcohol and adding one equivalent of alcoholic hydrochloric acid.

Example 7 6.21 grams of 2-(B-diethylamino-ethylarnino)aniline are added to a solution of the iinino-ether hydrochloride of parapropyloxy-phenylacetic acid obtained from 5.25 grams of para-propyloxy-benzyl cyanide, 1.73 cc. of absolute alcohol in 40 cc. of chloroform by introducing dry hydrogen chloride gas at 10 C. and allowing the whole to stand for 16 hours at 25 C. and then the whole is boiled under reflux for 16 hours while stirring. The reaction mixture is evaporated in vacuo, the residue is taken up in aqueous hydrochloric acid, and the acid solution is washed with ether, rendered alkaline with ammonia solution, extracted with chloroform, and the chloroform extract is washed with sodium carbonate solution, dried with magnesium sulfate, and evaporated. The crude l- B-diethyl-aminoethyl) 2- para-propyloxybenzyl) benzimidazole so obtained is converted into its hydrochloride, melting at 115-116 C., by dissolving the base in alcohol and adding two equivalents of alcoholic hydrochloric acid. 1

Example 8 6.21 grams of -2-(fl-diethylamino-ethylamino)aniline are added to' a solution of the imino-ether hydrochloride of para butyloxy phenylacetic acid, obtained from 5.68 grams of para butyloxy benzyl cyanide (prepared as described in our patent rpplication Ser. No. 684,360. filed September 19, 1957). 1.73 cc. of absolute alcohol and 40 cc; of chloroform by introducing dry hydrogen chloride gas at 10 C. and allowing the mixtureto stand for 16 hours at 25 C. The whole is then boiled under reflux for 16 hours while stirring. The reaction mixture is evaporated in vacuo, the residue is taken up inaqueous hydrochloric acid, the acid solution is extracted with ether, rendered alkaline with aqueous ammonia, extracted with chloroform, and the chloroform extract is washed with sodium carbonate solution, dried over magnesium sulfate, and evaporated. The crude l- (B diethylaminoethyl) 2 (para butyloxy benzyl)- benzimidazole so obtained is converted into its hydrochloride, melting at l29-l30 C;, by dissolving the base in alcohol and adding one equivalent of'alcoholic hydrochloric acid.

Example 9 16 hours, are added 12.0 grams of Z-(B-diethylamino ethylamino)5-chloraniline and the whole is stirred for 16 hours under reflux. The reaction mixture is evaporated-under vacuum, the residue dissolved in aqueous are added'to a solution of the'imino-ether hydrochloride hydrochloric acid, the acid solution washed with ether,

rendered alkaline with aqueous ammonia, then extracted with chloroform extract, after washing withsodiumcarbonate solution and drying overmagnesium sulfate, evap orated. The residue of crude 1-(fl-diethylaminoethyl)2- (p-ethoxy-benzyl) 5 chloro-benzimidazole is converted into the hydrochloride of M.P.,205207"C by dissolving in alcohol and-adding two equivalents of alcoholic hydroquired as starting material can be prepared as follows:

200 grams of 2:5-dichlornitrobenzene are introduced slowly with stirring at 140150 C. into 300 cc. of 5-diethylamino-ethylamine and then stirring continued for a further 2 hours at 140-150 C. The whole is then cooled to 70 C. and poured into ice water. The separated 2-(,B diethylamino-ethylamino)-5chloronitrobenzene, after recrystallization from methanol-water, melts at 51-52 48 grams of 2-(B-diethylamino-ethylamino)-5-chloron1 trobenzene, dissolved in 500 cc. of alcohol, are shaken in a hydrogen atmosphere with 5 grams of Raney nickel catalyst at 25 C. After 12 liters of hydrogen have been taken up the process is interrupted and the product filtered from catalyst, evaporated under vacuum and the crude 2- ,B-diethyl-amino-ethylamino) -5-chloroaniline distilled at 132-137 C. under 0.15 mm. pressure.

Example v To a solution of the imino ether hydrochloride of p- The 2-(B-diethylamino-ethylamino)-5-chloraniline re- .methoxy-phenyl acetic acid obtained from 7.4 grams of pmethoxy-benzyl cyanide, 2.9 cc. of absolute alcohol and 50 cc. of chloroform by the introduction of dry hydrochlorie acid gas at 10 C. and allowing to stand at C. for 16 hours, are added 12.0 grams of Z-(B-diethylamino-ethylarnino)-5-chloraniline and the whole is stirred for 16 hours under reflux. orated under vacuum, the residue dissolved in aqueous hydrochloric acid, the acid solution, washed with ether, rendered alkaline with aqueous ammonia, then extracted with chloroform and the chloroform extract, after washing with sodium carbonate solution and drying over magnesium sulfate, evaporated. The resulting l-(fl-diethylamino ethyl) 2 (p niethoxy benzyl) 5 chlorobenzimidazole is converted into its hydrochloride of MP. 183184 C. by dissolving in alcohol and adding one equivalent of alcoholic hydrochloric acid.

Example 11 A solution consisting of 5.88 grams of para-methoxybenzyl-cyanide, 2.32 ml. of absolute alcohol-and 40 cc.

for 12 hours at room tem- 8.3 grams of 2-(B- diethylamino-ethylamino)- dissolved'in 50 ml. of chloroform are added and the whole is boiled under reflux for 12hours.

The chloroform solution is evaporated, the residue is'agitated with a mixture of 50 ml. of water, 5 ml. of concentrated ammonia solution and 150ml. of ether. The ether extract is' 'washed with water and-extracted three'times with ml. of 1 N-hydrochloric acid. The hydrc x zhloric 7 acid extract is rendered alkaline with sodium hydroxide solution and the liberated base taken up in ether, dried and evaporated. By taking it up in a littleethanol and adding one equivalent of alcoholic .hydrochloricacid, 1-

(5 diethylamino ethyl) 2 (para -fmethoxy benzyl)- 5 :6-dichloro benzimidazole hydrochloride melting at 220 C. is obtained.

Example 12 Y A solution consisting of 3.2 grams of para-ethoxybenz yl "cyanide, 1.16 ml. of absolute alcohol and-20 mlu of chloroform is satuarted with dry hydrochloric acidjgas at 0 C. and allowed to stand for 12 hours at room temperaw ture. 5.5 grams of2-(fi-diethylarninoethylamino) 4:5- dichloro-aniline in 50 ml. of chloroform are added and the whole is boiled under reflux for 12 hours. Thechloroform solution is evaporated, and *theresidue agitated with a mixture of 30 cc. of water,f5 cc. of' concentrated ammonia solution and 100 cc. of ether. The ether extract is washed with water and extracted three times with 20 ccfiof 1 N-hydrochloric acid. The hydrochloric acid extract is'rendered alkaline with sodium hydroxide: solution andthe liberatedbased taken up in ether, the ether solution dried and evaporated. By takingit'iupfin' a little The reaction mixture is evapalcohol and adding one equivalent of alcoholic hydrochloric acid 1 (B diethylamino-ethyl)-2-(para-ethoxybenzyl)-5:6-dichloro-benzimidazole hydrochloride melting at 115 C. is obtained.

5 Example 13 7.2 grams of 2-(B-diethylamino-ethylamino)-5-chloraniline are added to a solution of the irnino-ether hydrochloride of para-methyl-phenylacetic acid, which has been '10 obtained from 3.95 grams of para-methyl-benzyl cyanide,

20 over magnesium sulfate and evaporated. The crude 1-(5- diethylamino ethyl) 2 (para methyl benzyl) 5- chloro-benzimidazole so obtained is dissolved in alcohol and converted into its hydrochloride crystallizing as solvate by the addition of one equivalent of alcoholic hy- 2 drochloric acid, the hydrochloride melting at 90- -110 C.

' Example 14 24 grams of 2-([i-diethylamino-ethylamino)-5-chloraniline are added to a solution of the imino-ether hydro- 30 chloride of para-ethyl-phenylacetic acid, which has been obtained from 14.5 grams of para-ethyl-benzyl cyanide, 5.8 cc. of absolute alcohol and 100 cc. of chloroform by lntroducing dry hydrochloric acid gas at 10 C. and allowing the whole to stand for 16 hours at 25 C., and then the whole is stirred for 16 hours under refluxf The reaction mixture is evaporated in vacuo, the residue dissolved in aqueous hydrochloric acid,-the acid solution washed with ether, rendered alkaline with aqueous ammonia, extracted with chloroform and the chloroform extract is washed with sodium carbonate solution, dried over magnesium sulfate and evaporated. The resulting crude 1-'(,8-

diethylamino ethyl) 2'- (para ethyl benzyl) 5- chloro-benzimidaz 'ole' is'distilled in a bulb tube at 190 200 C. and under 0.1 pressure of mercury as a' colorless v scous 011. -By neutralization with the calculated quantrty of hydrochloric acid an aqueous solution of 'the hydrochloride can be prepared.

3.93 grams of'para-methyl-b'enzyl cyanide in 1. 75 cc.

dry hydrochloric acid gas at 0 C. andl'the whole allowed to stand for 12 hours at room temperature. .4.14 grams 2'- (B dlethylamino ethylamino) 4z5-dichloraniline are added tofthe mixture, thewhole is boiled under reflux for 12 hours and evaporated. The residue'is taken'up in a mixture of 50cc. of 2 N-aqueous ammonia solution and 5250 cc.- of ethyl acetate. The organic-layer is extracted with 50 cc. of 2 N-sulfuric acid. From the aqueous :layer the base-is liberated with sodium hydroxide solution, taken in ethyl acetate; dried and freed frointhe solvent. The resulting 1' (fl-diethylaminoethylY 2 .(para-rnethyl-ben- 'Zyl)-5:6-dichloro-benzimidazole is converted into its hydrochloride melting at 235 C. by being dissolved in a1- fl5 cohiol and adding one equivalent of alcoholic hydrochloric Example 16 i 4.8 grams ofpara-(n),-propy1-benzy1 cyanide in 1.75 cc.

700 f ethanol and 40 cc. .of chloroform are saturated at 0 C.'with dry hydrochloric acid gas and the whole is allowed added and the mixture is boiled under refiux' forf12 hours .175 andevaporated. .The. residue is'taken up ina mixtuteof of ethanol. and 40 cc. of chloroform are saturated with 1 ..tic'- soda.

crude 2X,o-diethylamino-ethylamino) -5-methyl-aniline is v V I i i V .75

7 50 cc. of 2 N-aqueous ammonia solution and 250cc. of ethyl acetate. The ethyl acetate layer is extracted with 5 cc. 'of 2 N-sulfuric acid. From the aqueous layer the base is liberated with sodium hydroxide solution, taken up in ethyl acetate, dried and freed from the solvent. The resulting 1 3 diethyl-amino-ethyl) 2 (para-(n)- -propyl-benzyl)-5:6-dichloro-benzimidazole is converted into its hydrochloride melting at 160 C. by being dissolved in alcohol and adding the calculated quantity of alcoholic hydrochloric acid.

Example 17 13.5 grams of 2-(fi-diethylamino-ethylamino)-5-chloraniline are added to a solution of the imino-ether hydrochloride of para-acetyl-phenylacetic acid, which has been obtained from 9.0 grams of para-acetyl-benzyl cyanide, 80 cc. of chloroform and 3.25 cc. of absolute alcohol by introducing dry hydrochloric acid gas at -10 C. and allowing the Whole to stand for 44 hours at C., and then the whole is stirred under reflux for 16 hours. The reaction mixture is evaporated in vacuo, the residue dissolved in aqueous hydrochloric acid, the acid solution washed with ether is rendered alkaline with aqueous ammonia, extracted with chloroform and the chloroform extract washed with sodium carbonate solution, dried over magnesium sulfate and evaporated. The resulting crude l- B-diethylamino-ethyl) -2- (para-acetyl-benzyl) -5 -chlorohenzimidazole can'be converted into the crystalline hydrochloride melting at 195196 C. by being dissolved in alcohol and adding the calculated quantity of alcoholic hydrochloric acid.

Example 18 6.7 grams of 2-(,B-diethylamino-ethylamino)-5-methylaniline are added to a solution of the imino-ether hydrochloride of para-methyl-phenylacetic acid, (which has been obtained from 3.95 grams of para-methyl-benzylcyanide, 1.75 cc..of absolute alcohol and cc. of chloroform by introducing dry hydrogen chloride gas into the mixture at .10 C. and allowing the whole to stand for 16 hours at 25? C.), and the Whole is boiled under reflux for 24 hours while stirring. The reaction mixture is evaporated in vacuo, theresidue is dissolved in aqueoushydrochloric acid, the acid solution iswashed with ethyl acetate,

then rendered alkaline with ammonia,'extracted with ethyl:

acetate,'the ethyl acetate extract solution is washed-with sodium carbonate solution and dried over magnesium sulfate, and then evaporated. The resulting crude l-(fl-diethylamino ethyl)-2-(para-methyl-benzyl) -5-rnethyl-'benzirriidazole is'lconverted into its hydrochloride melting at "1'51..l53":C. by dissolution in alcohol and-the addition ofthe calculated. quantity of hydrochloric acid inethyl acetate. l v v The. 2-('Badiethylannnoethylamino) '5 methyl aniline used asrstartingmaterial can be prepared-as follows:

68.6 grams of'3rriitro-4-chlorotoluene are slowly introducedwhile stirring at 130 C. into 92.8 grams of fl-dreth ylamino-ethylamine, and then the whole is stirred. for a further 3 hours at 150 C. The mixture is then cooled to70 1C..and poured intoqa cold aqueous solution of caus- 37 m s of' 2(B-diethylannno-ethylamino) 5-methylnitrobenzene, dissolved in 500 ccof alcohol, are agltated. in an atmosphere of hydrogen with 5 grams of Fancy nickel at 25 C. When 245 liters of hydrogen havebeen absorbed, the hydrogenation is interrupted, the catalyst 8 7 Example 19 11 'g. of 2-(B-diethylamino-ethylarnino)-5-methylaniline are added to a solutionof the imino ether hydrochloride of para-acetyl-phenyl acetic acid obtained from 8.0 g. of para-acetylbenzyl cyanide, 2.9 ml.-of absolute alcohol in ml. of chloroform by introducing dry hydrogen chloride gas at l0 C. and allowing the reaction mass to stand at 25 C. for 16 hours. The whole is boiled under reflux for 18 hours. It is then evaporated and the residue taken up in hydrochloric acid, the acid solution extracted with ether and rendered alkaline with aqueous ammonia, extracted with chloroform, the extract Washed with sodium carbonate solution and dried over magnesium sulfate, and evaporated. The resulting crude l-(fi-diethyh amino-ethyl)-2-(para-acetylbenzyl) 5 methyl-benzimidazole is converted into the hydrochloride of melting point 178-179 C. by dissolving it in alcohol and adding the calculated quantity of alcoholic hydrochloric acid.

6 of 1-(6 diethylamino ethyl) 2 (para acetyl benzyl)-5-methyl-benzimidazole-hydrochloride are dissolved in 200 ml. of 90% methanol and 3 g. of sodium borohydrate introduced slowly. When the reaction has subsided, 'the reaction mass is refluxed for 3 hours. It

is then evaporated under reduced pressure, the residue taken up carefully in hydrochloric acid, extracted with ether, and the acid aqueous solution rendered alkaline with ammonia. The solution is then extracted with chloroform and the extract washed with sodium carbonate solution, dried over magnesium sulfate, and evaporated. The resulting l-(fi-diethylamino ethyl-2-[para-(1'-hydroxy-ethyl)-benzyl]-5-methyl-benzimidazole melts at 136 C.

4 g. of l-(B-diethylamino-ethyl)-2-[para-(1'-hydroxyethyl)-benzyl]-5-methyl-benzimidazole are refluxed for 14 hours in 100 ml. of 47% hydriodic acid in the presence of 3 g. of red phosphorus. The reaction mass is filtered, concentrated under reducedpressure, the concentrated solution rendered alkaline with sodium hydroxide solution, extracted with chloroform, the extract dried over magnesium sulfate, and evaporated. The residue is taken up in alcohol and agitated in an atmosphere of hydrogen .inthe presence of a platinum catalyst until nov more gas Thelmixtureisgextracted with ether, and the ethereal solution is washed with water and dried over is filtered off; the filtrate is evaporated in vacuo, and the distilled at 128-132" C5 undr0.06- Tor.

v Example 20 A mixture of 7.86 of para-methyl-benzyl-cyanide, 3.5

ml. of ethanol and ml. of chloroform is saturated with dry hydrogen chloride gas at 0 C., allowed to stand at room temperature for 12 hours, then admixed with 6.8 g.' of 2-amino-4:S-dimethyl-aniline, and boiled .under reflux for 12 hours,

' After. cooling, the, reaction. mixture is vigorously agitated with 100ml. of N-aqueous ammonia solution, the clear chloroform layer is separated, dried with magnesium sulfate, evaporated, and the residue recrystallized from ethyl acetate.

The resulting 2-(para-methyl-benzyl)-5:G-dimethylbenzimidazole melts at 200 C.

2.5 g. of Z -(para-methyI-benZyD-S:6-dimethyl-benzimidazole, dissolved in 50ml. of dioxane are mixed with 0.4 g. of sodamide at 70 C. At the same temperature, 1.4 g. of fi-diethylamino-ethyl chloride, dissolved in 10 ml. of dioxane are added dropwise inthe course of half an hour. When the addition is complete, the reaction .mixtureis kept at 70 C. for 2 hours and, after the addidrochloric acid an aqueous solution of its hydrochloride can be prepared. h

, Example 21 To a solution of the imino-ether hydrochloride of paraethoxy-phenyl acetic acid, whichhas been obtained from 8.05 grams of para-ethoxy-benzyl cyanide, 2.9 cc. of absolute alcohol and 60 cc. of chloroform by introducing dry hydrogen chloride gas into the mixture at -10 C. and allowing the whole to stand for 16 hours at 25 C., there are added 11.1 grams of Z-(fl-diethylamino-ethylamino)-5-methyl-aniline and the whole is boiled for 16 hours under reflux while stirring. The reaction mixture is then evaporated in vacuo, the residue is dissolved in aqueous hydrochloric acid, the acid solution is washed with ethyl acetate, then rendered alkaline with aqueous ammonia, extracted with ethyl acetate, and the ethyl acetate extract is washed with sodium carbonatesolution, dried over magnesium sulfate and evaporated. The residue is distilled in a high vacuum, whereby 1-(,8-diethylaminoethyl) 2 (para-ethoxy-benzyl)-5-methylbenzimidazole is obtained in the form of a slightly yellow thickly liquid oil boiling at 200-205 C. under 0.05 Tor.

A dihydrochloride of the base melting at 93-95 C. is obtained by reacting an alcoholic solution of the base with two equivalents of hydrochloric acid in ethyl acetate.

The 2 (B-diethylamino-ethylamino)-5-methyl-aniline used as starting material may be prepared as follows:

68.6 grams of 3-nitro-4-chlorotoluene are slowly introduced while stirring at 130 C. into 92.8 grams of fi-diethylamino-ethylamine, and then the whole is stirred for a further 3 hours at 150 C. The mixture is then cooled to 70 C. and poured into a cold aqueous solution of caustic soda. The whole is extracted with ether and the ethereal solution is washed with water and dried over magnesium sulfate. After distilling oil the solvent, the residue is distilled in a high vacuum whereby 2-(13- diethylamino-ethylamino)-5-methyl-nitrobenzene is obtained as a thickly liquid red oil boiling at 140145 C. under 0.05 Tor.

87 grams of 2-(fl-diethylamino-ethylamino)-5-methylnitrobenzene, dissolved in 500 cc. of alcohol, are agitated in an atmosphere of hydrogen with 5 grams of Raney nickel at 25 C. When 24.5 liters of hydrogen have been absorbed the hydrogenation is interrupted, the catalyst is filtered off, the filtrate is evaporated in vacuo, and the crude 2-(,B-diethylamino-ethylamino)-5-methyl-aniline is distilled at 128-132 C. under 0.06 Tor.

Example 22' To a solution of the imino-ether hydrochloride of para-ethoxy-phenylacetic acid, which has been obtamed from 6.5 grams of para-ethoxy-benzyl cyanide, 2.3 cc. of

absolute alchool and 50cc. of chloroform by introducing dry hydrogen chloride gas into the mixture at 10 C. and allowing the whole to stand for 16 hours at 25 0., there are added 8.8 grams of 2- (fl-diethylamino-ethylamino)-4-methyl-aniline,v and the whole is boiled under reflux for 24 hours while stirring. The reaction mixture is evaporated in vacuo, the residue is dissolved in aqueous hydrochloric acid, the acid solution is washed with ethyl acetateand rendered alkaline with aqueous ammonia, then extractedwith chloroform and the chlo reform extract is washed with sodium carbonate solution,

. r r 10 dried over magnesium sulfate and evaporated. The residue is distilled in a high vacuum, whereby l-(fi-diethylamino-ethyl) 2 (para-ethoxy-benzyl)-6-methyl-benzimidazole is obtained in the form of a slightly yellow thickly liquid oil boiling at 210-215 C. under 0.05 Tor. The hydrochloride of the base melting at 170l73 C. is obtained by reacting an alcoholic solution of the base with 1 equivalent of hydrochloric acid in ethyl acetate.

The 2 (/3 diethylamino ethylamino) 4 methylaniline used as starting material is prepared by the method used in Example 1 for preparing Z-(B-diethylaminoethylamino)-5-methylaniline, by using 3-chloro-4-nitro toluene and B-diethylamino-ethylamine as starting materials, and the product is a slightly yellow oil boiling at 114ll8 C. under 0.03 Tor.

Example 23 To a solution of the iminoether hydrochloride of paramethylmercapto-phenylacetic acid, which has been obtained from 4.9 grams of para-methylmercapto-benzyl cyanide, 1.75 cc. of absolute alcohol and 30 cc. of chloroform by introducing intothe mixture dry hydrogen chloride gas at 10 .C. and allowing the whole to stand for 16 hours at 25 C., there are added 6.7 grams of Z-(B- diethylamino ethylamino) 5 methyl-aniline, and the whole is boiled under reflux for 24 hours while stirring. The reaction mixture is evaporated in vacuo, the residue is dissolved in aqueous hydrochloric acid, the acid solution is washed with ethyl acetate and rendered alkaline with aqueous ammonia, then extracted with ethyl acetate, and the ethyl acetate extract solution is washed with sodium carbonate solution and dried over magnesium sulfate and evaporated. The residue is distilled in a high vacuum, whereby 1 (fl diethylamino ethyl) 2 (para methyl-mercapto benzyl) 5 methyl benzimidazole is obtained in the form of a slightly yellow thickly liquid oil boiling at 210-215 C. under 0.02 Tor.

The base is dissolved in alcohol and its hydrochloride melting at 205207 C. is obtained by adding one equivalent of hydrochloric acid in ethyl acetate.

The para-methylmercapto-benzyl-cyanide used as starting material is prepared as follows:

26 grams of para-methylmercapto-benzyl chloride are boiled, while stirring, in 150 cc. of acetone with 21.5 grams of potassium cyanide and l gram of potassium iodide for 16 hours. After filtering the mixture and evaporating the filtrate, the residue is taken up in ether and the ethereal solution is washed with water. The ethereal solution is then dried with magnesium sulfate, and evaporated to yield para-methylmercapto-benzyl cyanide boiling at 116-120 C. under 0.07 Tor. and melting at 44-45" C.

Example 24 2.4 grams of sodamide are introduced in' portions into a stirred suspension of 14 grams of Z-(para-ethoxy- ,benzyl)-5:6-dimethyl benzimidazole in ml. of absolute dioxane, and the mixture is boiled under reflux until the evolution of ammonia can no longer be detected. 8.2 grams of chlor-ethyl-diethylamine are then slowly introduced dropwise ,at 60-70 C., and the whole is stirred for a further 16 hours at that temperature. Residual sodamide is decomposed by introducing alcohol dropwise, the reaction mixture is evaporated, the residue is taken up in dilute hydrochloric acid, the acid solution is filtered to remove unreacted starting material, and the filtrate is extracted with ether, rendered alkaline with aqueous ammonia and extracted with chloroform. The

. chloroform extractsolution is washed with sodium carbonate solution and dried over magnesium sulfate, and

is evaporatedto yield crude 1-(,fi-diethylamino-ethyl)-2- (para-ethoxy-benzyl)-5i6-dimethylbenzimidazole. 'By dishydrochloride melting at 167-468 C. obtained. 1

. Ill

The 2 (para ethoxy benzyl) 5:6 dimethyl benzimidazole used as starting material may be prepared as follows:

The imino-ether hydrochloride of para-ethoxyphenylacetic acid (obtained from 14.5 grams of para-ethoxy benzyl cyanide and 5.8 ml. of alcohol in 100 ml. of chloroform by introducing dry hydrogen chloride into the mixture at -10 0., allowing the mixture to stand for 16 hours at 25 C., and evaporating the mixture in vacuo) is boiled under reflux with 13.6 grams of 2-amino- 4-:5-dimethylaniline in 100 ml. of chloroform for 6 hours while stirring. The reaction mixture is evaporated in vacuo, the residue is taken up in sodium carbonate solution, and the precipitated 2-(para-ethoxy-benZyl)-5:6- dimethylbenzimidazole is filtered off with suction. After recrystallization from ethanol, the product melts at 205-206 C.

Example 25 To a solution of the iminoether hydrochloride of paramethoxy-phenylacetic acid, which has been obtained from 7.5 grams of para-methoxy-benzyl cyanide, 2.9 cc. of absolute alcohol and 50 cc. of chloroform by introducing into the mixture dry hydrogen chloride gas at l(i C. and allowing the whole to stand for 14, hours at 25 C., there are added 11 grams of 2-(fl-diethylamino-ethylamino)-5-methyl-aniline, and the whole is boiled under reflux for 18 hours with stirring. The reaction mixture is evaporated, taken up in aqueous hydrochloric acid, the acid aqueous solution extracted with ether is rendered alkaline with aqueous ammonia, ex tracted with chloroform, and the chloroform extract washed with sodium carbonate solution, dried with magnesium sulfate and evaporated. The resulting crude 1- (p diethylamino ethyl) 2 (para methoxy benzyl)- S-methyl-benzimidazole is converted into the hydrochloride melting at 147-148 C. by being dissolved in alcohol and adding the calculated quantity of alcoholic hydrochloric acid.

What is claimed is:

wherein R and R stand for a member selected from the group consistingof hydrogen, chlorine and the methyl group, and R for a member selected from the group consisting of lower alkoxy, lower alkylmercapto, lower alkyl and lower alkanoyl, and their therapeutically useful acid addition salts.

2. 1 (B diethylaminoethyl) 2 para n propylbenzyl) benzimidazole.

3. 1 (B diethylaminoethyl) 2 (para ethoxybenzyl) benzimidazole.

4. 1 (B diethylaminoethyl) 2 (para ethoxybenzyl) 5 chloro benzimidazole.

5. 1 (/3 diethylaminoethyl) 2 (para ethoxybenzyl)'- 5,6 dichloro benzimidazole.

6. 1 (5 diethylaminoethyl) 2 (para acetylbenzyl) 5 methylbenzimidazole.

7. 1 (,3 diethylaminoethyl) 2 (para ethoxybenzyl) 6 methyl benzimidazole.

8. 1 (,8 diethylaminoethyl) 2 (para methylmercapto benzyl) 5- methyl benzimidazole.

9. 1 (fi diethylaminoethyl) 2 (para ethoxybenzyl) 5,6 dimethyl benzimidazole.

Wright: J. Am. Chem. Soc., vol. 71, pp. 2035-2037 -1949 a Novelli: Chem. Abstracts, vol. 49, col. 1021 (1955'); 

1. BENZIMIDAZOLES OF THE FORMULA 